Evidence of class I HDACs inhibition and cell cycle block in human carcinoma cells after (R) or (S)-9- HSA treatment

It has been reported that the interaction of the two enantiomers of 9-HSA with the catalytic site of hystone deacetylase, using a molecular modelling approach, is different. The interaction energy of the (R) enantiomer was lower as compared with the (S) indicating a more stable complex formation (N. Calonghi et al 2005). In this work (R) and (S)-9HSA were isolated and their biological activity tested in HT29 cell line. The conclusions that can be drawn from this work can be summarized as follows: (i) Both enantiomers inhibit the enzymatic activity of HDAC1, HDAC2 and HDAC3, being (R) more active; (ii) (R) and (S) inhibitory effect induces an increase in histone H4 acetylation; (iii) the antiproliferative effect induced by (R) is more pronounced as much as the increase of p21 transcription and protein level, while the expression of Cyclin D1 is decreased. It can be hypothesized that the interaction of (R)-9HSA with HDAC1 may induce conformational changes in the enzyme causing loss of its interaction with other proteins, like cyclin D1 that, being released from the complex, can be ubiquitinated, thus losing the interaction with CDK and thereby stopping the cell proliferation.